The GABAA receptor is a receptor of the chief inhibitory neurotransmitter in the central nervous system. The GABAA receptor is composed of a pentamer of transmembrane polypeptide subunits, and 19 different subunits assemble into various GABAA receptor subtypes. The GABAA receptor is involved in pathogenesis, diagnosis and treatment of various conditions such as anesthesia, depression, anxiety, epilepsy, memory disorders, and drug dependence, and has accordingly become a pharmacologically and clinically important target for drugs. Propofol and its derivatives represent a marked class of GABAA-targeting compounds.
Propofol can activate many GABAA receptor subtypes, and is a clinically sophisticated venous anesthetic widely used for induction and maintenance of general anesthesia. Clinical dosage-related propofol can directly activate the GABAA receptor-chloride channel complex in mammalian neurons, thereby enhancing transportation of Cl−, reducing excitability of the neural network, and in turn inducing general anesthesia (Manami Hara, et al., (1993) Anesthesiology, 79, 781-788). Propofol shows remarkable pharmacokinetic and pharmacodynamic characteristics in that it rapidly takes effect, acts for a short period, and is quickly reversible. Upon intravenous administration, propofol in the blood rapidly enters hyperperfusion sites such as heart, lung and liver, and its high liposolubility allows propofol to easily travel across the blood-brain barrier into the brain to affect general anesthesia.
However, propofol has obvious limitations and disadvantages. It has been reported that approximately 70% of patients on propofol injections feel certain pain or discomfort (Pascale Picard (2000) Anesthesia & Analgesia, 90, 963-969), which is reportedly believed to be injection-induced pain caused by propofol in the aqueous phase of a lipid emulsion (Klement W, et al., 1991, Br J Anaesth 67, 281). Several studies have reported that a decreased concentration of propofol in the aqueous phase, as compared to the propofol content in the aqueous phase of DIPRIVAN, results in significantly less pain on injection (Doenicke A W, et al., 1996, Anesth Analg 82, 472; Ueki R, et al., 2007, J Anesth 21, 325). Although it is also reported that pre-treatment with other drugs or combined administration of drugs may reduce the incidence and severity of pain on propofol injections (C. H. Tan, et al., (1998) Anaesthesia, 53, 302-305), such pain is still unavoidable. It has been demonstrated that propofol can lower the systolic pressure, the diastolic pressure, and the mean arterial pressure, and thus may clinically cause hypotension. Furthermore, respiratory depression is also an unneglectable risk upon use of propofol. These adverse effects have considerably impeded application of propofol in certain clinical cases, such as cardiovascular diseases, brain injury, and chronic hypotension.
Fospropofol is a water-soluble prodrug of propofol, and can be rapidly hydrolyzed by alkaline phosphatase to release propofol, phosphate, and formaldehyde. Although fospropofol relieves pain at sites of intravenous propofol injection, it still poses risks of respiratory depression and adverse haemodynamic effects (Cohen L B (2008) Aliment Pharmacol Ther, 27, 597) because it takes effect in the form of the active compound propofol. In addition, fospropofol may also cause abnormal sensation and itching.
Because of the limitations and disadvantages of propofol and fospropofol, there is a need for developing novel GAGAA-receptor agonist possessing better pharmacokinetic and pharmacodynamic characteristics and fewer side effects. An objective of the present invention is to introduce a new group of propofol derivatives that take effect faster, act for a similar period, and have a greater therapeutic index as compared to propofol, and also reduce the likelihood of pain on injection thanks to their increased liposolubility (A W Doenicke, et al., (1996) Anesth Analg, 82, 472-474).
WO2009140275 describes a propofol analog or a pharmaceutically acceptable salt thereof, useful as an anesthetic, wherein X may be a hydrogen or fluorine atom. The general formulae of the compounds of this invention are shown below:
which are structurally very different from the compounds of the present invention.
EP1206934 describes a phenol derivative or a pharmaceutically acceptable salt or prodrug thereof, useful for local anesthesia, anti-arrhythmia and anti-convulsion, wherein, R1, R3, R4, R5 and R6 each are a hydrogen atom, a halogen atom, or C1-7 alkyl; R2 is C1-7 alkyl or hydroxyl; alternatively, R1 and R2 may optionally form a 5- or 6-membered ring. The general formula of the compound of this invention is shown below:
which is structurally very different from the compound of the present invention.
WO03026632 describes a phenol derivative or a pharmaceutically acceptable salt thereof, useful for anesthesia and sedation, wherein R1 and R2 are each independently selected from C1-8 alkyl or C1-8 cycloalkyl; L is selected from a covalent bond or C1-12 hydrocarbylene; and R3 is selected from —C(═O)ORa, wherein Ra is selected from C1-12 hydrocarbyl. The general formula of the compound of this invention is shown below:
which is structurally very different from the compounds of the present invention. The specific descriptions in WO03026632 are not considered as part of the present invention.
WO2008008492 describes a substituted hydrofluoroalkyl phenol compound and a pharmaceutically acceptable salt or prodrug thereof, useful as an anesthetic, wherein R1 is a substituted or unsubstituted branched C3-6 alkyl; R2 is a hydrogen atom, or a substituted or unsubstituted C1-3 alkyl; R3 is a C1-3 fluoroalkyl. As defined in its specification, alkyl refers to a saturated aliphatic group, including linear, branched and cyclic alkyl groups; a substituted alkyl refers to an alkyl in which one or more hydrogen atoms on a carbon atom have been substituted with substituents, and the substituents include fluorine, chlorine, bromine, iodine, hydroxyl, alkoxy, cyano, amino, mercapto, alkylthio, nitro, and azido. The general formula of the compound of this invention is shown below:

The specific descriptions in WO2008008492 are not considered as part of the present invention.
WO2006106906 describes preparation of a cyclopropyl phenol derivative represented by the general formula below,
wherein R1, R2, R3, and R4 may each independently be hydrogen, F, Cl, Br, I, optionally substituted C1-6 alkyl, etc.; Z is hydrogen, optionally substituted C1-6 alkyl, etc.; Y1, Y2 and Y3 are hydrogen atoms. The specific descriptions in WO2006106906 are not considered as part of the present invention.